Process for preparation of bisphosphonic acid compounds

ABSTRACT

The present invention provides a novel process for preparation of bisphosphonic acids or salts thereof, e.g. alendronic acid, by reacting a carboxylic acid, phosphorous acid and a halophosphorous compound in a water miscible neutral solvent.

The present invention relates to an improved process for preparation ofbisphosphonic acid compounds, represented by a compound of formula 1 orsalts thereof. More specifically the present invention relates to aprocess for preparation of compound of formula 1 or a salt thereof byreaction of a carboxylic acid compound of formula 2 or a salt thereofwith a mixture of phosphorous acid and phosphorous trichloride (PCl₃) insulfolane.

The present invention particularly relates to a process for thepreparation of bisphosphonic acid compounds of formulae 3 to 10, namely,alendronic acid, pamidronic acid, risedronic acid, zoledronic acid,ibandronic acid, minodronic acid, neridronic acid and olpadronic acid,respectively or salts thereof.

Bisphosphonate compounds have generally been prepared by the reaction ofcarbonyl compounds with phosphorous halides.4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid (alendronic acid, acompound of formula 3) or salts thereof are prepared by the reaction of4-aminobutyric acid with a mixture of phosphorous acid and one of thethree phosphorous chlorides; viz. phosphorous trichloride (PCl₃),phosphorous oxychloride (POCl₃) or phosphorous pentachloride (PCl₅),then quenching the reaction mixture with water followed by heating tohydrolyze the phosphorous intermediates.

Different processes using a variety of different solvents/carriers havebeen reported in the literature for making the reaction mixturehomogenous for preparation of bisphosphonates, however they have somedisadvantages associated with their use.

U.S. Pat. No. 4,407,761 (referred to herein as the '761 patent) teachespreparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acidbesides other phosphonic acids. However, high amounts of yellow-orangesolid containing monophosphoric acid, phosphorous acid and differentphosphonic acids, which is sticky, non-stirrable is generated. Hence,the process in not convenient for industrial scale production. Further,in the '761 patent chlorobenzene is used as the reaction medium, whichis harmful, an irritant for skin, eyes and environmentally hazardous.

U.S. Pat. No. 4,705,651 teaches a similar procedure with different molarratios, which is still not very attractive for industrial scale up.

U.S. Pat. Nos. 4,922,007 and 5,019,651 teach the use of methanesulfonicacid for solubilizing the reaction components. Methanesulfonic acid isexpensive, corrosive and irritant. The reaction between methanesulfonicacid and PCl₃ is exothermic, which could pose problems in commercialscale operations. Also, large quantity of alkali would be required inthe work up for neutralization.

U.S. Pat. No. 5,908,959 teaches use of long chain glycols to attempt toprevent the solidification of the reaction mixture, however thesolidification cannot be totally avoided and these glycols cannot berecycled as they get converted to their corresponding chloridederivatives, which could be potentially toxic.

The PCT application WO 02/090367 teaches use of aralkyl or alkylethoxylates or triglycerides such as plant or animal oils forsolubilization of the reaction mixture.

United States Patent Application No. 2003/0013918 teaches the use of anamine hydrochloride in preparation of bisphosphonates from the reactionof a carbonyl compound with a phosphorous halide. This process involvesuse of concentrated hydrochloric acid as a reactant.

United States Patent Application No. 2004/0043967 discloses use ofaromatic hydrocarbon or a silicone fluid as a diluent for preparation ofbisphosphonic acids.

The present invention provides a process wherein a water miscibleneutral solvent such as sulfolane is used for preparation ofbisphosphonic acid compounds, making the process safe and convenient. Wehave also found that water miscible neutral ether solvent such as1,2-dimethoxyethane, 1,4-dioxane, glymes such as diglyme and the likecan also be used for preparation of bisphosphonic acids, howeversulfolane was observed to provide superior yields. The process of thepresent invention is suitable for industrial scale up and can be usedcommercially. Since sulfolane is water miscible and neutral, thereaction mixture can be conveniently worked up by quenching into water,the intermediates subsequently hydrolyzed and the final bisphosphonicacid product directly isolated from the reaction mixture, if desired inthe form of a salt thereof.

SUMMARY OF THE PRESENT INVENTION

A process for preparation of bisphosphonic acid, a compound of formula 1or a salt thereof,

comprising reacting a carboxylic acid compound of formula 2 or a saltthereof

-   -   wherein,    -   A is a straight chain alkyl, a branched alkyl or a cyclic alkyl        chain with up to 10 carbon atoms, which can optionally contain        hetero atoms in between and,    -   B is alky, aralkyl, aromatic or heteroaromatic group, which can        be optionally substituted;    -   or    -   wherein, R₁ and R₂ may be selected from hydrogen or straight        chain, branched or cyclic lower alkyl,        with phosphorous acid and a phosphorous chloride selected from        PCl₃, PCl₅ and POCl₃, in sulfolane.

In first aspect the present invention provides a process comprisingreacting 4-aminobutyric acid with phosphorous acid and a phosphorouschloride selected from PCl₃, PCl₅ and POCl₃, in sulfolane to preparealendronic acid.

In second aspect the present invention provides a process comprisingreacting 3-aminopropionic acid with phosphorous acid and a phosphorouschloride selected from PCl₃, PCl₅ and POCl₃, in sulfolane to preparepamidronic acid.

In third aspect the present invention provides a process comprisingreacting 3-pyridylacetic acid with phosphorous acid and a phosphorouschloride selected from PCl₃, PCl₅ and POCl₃, in sulfolane to preparerisedronic acid.

In fourth aspect the present invention provides a process comprisingreacting 1-imidazolylacetic acid with phosphorous acid and a phosphorouschloride selected from PCl₃, PCl₅ and POCl₃, in sulfolane to preparezoledronic acid.

In fifth aspect the present invention provides a process comprisingreacting N-(n-pentyl)-N-methyl-3-aminopropionic acid with phosphorousacid and a phosphorous chloride selected from PCl₃, PCl₅ and POCl₃, insulfolane to prepare ibandronic acid.

In sixth aspect the present invention provides a process comprisingreacting 2-(imidazo[1,2-a]pyridin-2-yl)ethanoic acid with phosphorousacid and a phosphorous chloride selected from PCl₃, PCl₅ and POCl₃, insulfolane to prepare minodronic acid.

In seventh aspect the present invention provides a process comprisingreacting 6-aminohexanoic acid with phosphorous acid and a phosphorouschloride selected from PCl₃, PCl₅ and POCl₃, in sulfolane to prepareneridronic acid.

In eighth aspect the present invention provides a process comprisingreacting 3-(dimethylamino)propionic acid with phosphorous acid and aphosphorous chloride selected from PCl₃, PCl₅ and POCl₃, in sulfolane toprepare olpadronic acid.

DETAILED DESCRIPTION OF INVENTION

The process of the present invention is characterized by preparation ofbisphosphonic acid, a compound of formula 1 or a salt thereof byreacting a carboxylic acid compound of formula 2 or a salt thereof withphosphorous acid and a halophosphorous compound in a water miscible andneutral solvent like sulfolane.

The moiety A is a straight chain, a branched alkyl chain or a cyclicalkyl chain with up to 10 carbon atoms, which can optionally containhetero atoms in between for e.g., oxygen and sulphur.

The moiety B may be an alkyl, aralkyl, aromatic or heteroaromatic group,that may be monocyclic or polycyclic for example, methyl, ethyl,isopropyl, benzyl, phenyl, pyridinyl, imidazolyl, indolyl,imidazopyridinyl and the like, that may be unsubstituted or substituted.

The substituents R₁ and R₂ both may be same or different and selectedfrom hydrogen or straight chain, branched or cyclic lower alkyl. Thelower alkyl are containing up to 5 carbon atoms for e.g. methyl, ethyl,isopropyl, cyclopropyl.

In the process of the present invention, the preferred halophosphorouscompound is a phosphorous chloride e.g. PCl₃. PBr₃, POBr₃ or PBr₅ canalso be used. The carboxylic acid compound of formula 2 or a saltthereof for example, hydrochloride salt can be used.

The bisphosphonic acids can be obtained in a safe manner, in high yieldand purity when using the process of the invention. The presentinvention uses sulfolane, which is relatively safe and inexpensive,water miscible neutral solvent for preparation of bisphosphonic acids.The hydrolysis of the formed phosphorous intermediates can be carriedout in same reaction mixture, and if desired, the pH can be adjustedsuitably, for example to about 4.3 and the sodium salt of thebisphosphonic acid can be directly obtained in pure form. It is observedthat the process of the present invention provides compounds of formulae4, 5 and 6 in improved yield and quality.

The compound of formula 2 and the phosphorous acid in sulfolane arereacted with phosphorous trichloride at a suitable temperature, forexample, between about 35° C. to about 150° C., preferably at about 60to about 70° C., at which temperature the phosphonylation reaction iscompleted in about 3 hours.

The reaction preferably is carried out by combining the carboxylic acidcompound with phosphorous acid in presence of sulfolane at a temperaturebetween about 70° C. and about 80° C. for a time between about 1 toabout 2 hours. To the reaction mixture at temperature of about 35° C. toabout 40° C., the halophosphorous compound like phosphorous chloride isadded in small portions. The reaction mixture is heated to a temperaturebetween about 60° C. to about 70° C., preferably about 65° C. to about67° C. for a period of about 2 to about 4 hours. The reaction mixturecontaining white solid is cooled to about 0° C. to about 5° C. Thenwater is added carefully to the reaction mixture to get a clearsolution, which is heated to about 100° C. for a period of about 3 toabout 4 hours. Thereafter the product bisphosphonic acid can be isolatedfrom the reaction mixture by any means known in the art. For example,the product may be precipitated by cooling to about 0° C. or bycombining with a solvent like acetone and isolated by filtration,centrifugation etc.

If it is desired to isolate the bisphosphonic acid as a sodium saltthereof, then after heating the clear solution to about 100° C. for aperiod of about 3 to about 4 hours as described above, the solution maybe cooled to about 0° C. to about 5° C. and thereafter the pH issuitably adjusted with a base like aqueous NaOH and the precipitatedsalt may be isolated by a manner known in the art. Alternatively, thebisphosphonic acid is suspended in water, pH is suitably adjusted with abase like aqueous alkali or alkaline metal carbonates and theprecipitated salt may be isolated by methods known in the art.

In the process of the present invention when:

4-aminobutyric acid is used, the product bisphosphonic acid isalendronic acid,

3-aminopropionic acid is used, the product bisphosphonic acid ispamidronic acid,

3-pyridylacetic acid, a compound of formula 11 is used, the productbisphosphonic acid is risedronic acid,

1-imidazolylacetic acid, a compound of formula 12 is used, the productbisphosphonic acid is zoledronic acid,

N-(n-pentyl)-N-methyl-3-aminopropionic acid is used, the productbisphosphonic acid is ibandronic acid,

2-(imidazo[1,2-a]pyridin-2-yl)ethanoic acid is used, the productbisphosphonic acid is minodronic acid,

6-aminohexanoic acid is used, the product bisphosphonic acid isneridronic acid,

3-(dimethylamino)propionic acid is used the product bisphosphonic acidis, olpadronic acid.

In one embodiment the present invention provides a process forpreparation of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid(alendronic acid), a compound of formula 3 or salt thereof by reacting4-aminobutyric acid with phosphorous acid and PCl₃ in sulfolane.

In a preferred embodiment alendronic acid monosodium trihydrate isprepared by a process comprising the steps of:

-   -   a) reacting 4-aminobutyric acid, phosphorous acid and        phosphorous chloride in sulfolane at a temperature of about        60° C. to about 70° C.    -   b) quenching the reaction mixture with water    -   c) heating the reaction mixture to about 100° C.    -   d) cooling and adjusting the pH to about 4.3    -   e) isolating alendronic acid monosodium trihydrate from the        reaction mixture.

In second embodiment the present invention provides a process forpreparation of 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid(pamidronic acid), a compound of formula 4 or salt thereof by reacting3-aminopropionic acid with phosphorous acid and PCl₃ in sulfolane. Theresultant pamidronic acid can be in-situ converted to disodium saltthereof or isolated and converted to disodium salt thereof.

In a preferred embodiment pamidronic acid disodium pentahydrate isprepared by a process comprising the steps of:

-   -   a) reacting 3-aminopropionic acid, phosphorous acid and        phosphorous chloride in sulfolane at a temperature of about        60° C. to about 70° C.    -   a) quenching the reaction mixture with water    -   b) heating the reaction mixture to about 100° C.    -   c) isolating pamidronic acid from the reaction mixture,    -   d) suspending pamidronic acid in water and adjusting the pH to        about 8.0    -   e) isolating pamidronic acid disodium pentahydrate.

In third embodiment the present invention provides a process forpreparation of 1-hydroxy-2-(3-pyridinyl)ethylidene-1,1-bisphosphonicacid (risedronic acid), a compound of formula 5 or salt thereof byreacting 3-pyridylacetic acid,

a compound of formula 11 with phosphorous acid and PCl₃ in sulfolane.The resultant risedronic acid can be in-situ converted to monosodiumsalt thereof or isolated and converted to monosodium salt thereof.

In a preferred embodiment risedronic acid monosodium is prepared by aprocess comprising the steps of:

-   -   a) reacting 3-pyridylacetic acid, phosphorous acid and        phosphorous chloride in sulfolane at a temperature of about        60° C. to about 70° C.    -   b) quenching the reaction mixture with water    -   c) heating the reaction mixture to about 100° C.    -   d) isolating risedronic acid from the reaction mixture    -   e) suspending risedronic acid in water and adjusting the pH to        about 4.3    -   f) isolating risedronic acid monosodium from the reaction        mixture.

In fourth embodiment the present invention provides a process forpreparation of 1-hydroxy-2-(imidazol-1-yl)ethylidene-1,1-bisphosphonicacid (zoledronic acid), a compound of formula 6 or salt thereof byreacting 1-imidazolylacetic acid,

a compound of formula 12 with phosphorous acid and PCl₃ in sulfolane.

In a preferred embodiment zoledronic acid monohydrate is prepared by aprocess comprising the steps of:

-   -   a) reacting 1-imidazolylacetic acid, phosphorous acid and        phosphorous chloride in sulfolane at a temperature of about        60° C. to about 70° C.    -   b) quenching the reaction mixture with water    -   c) heating the reaction mixture to about 100° C.    -   d) isolating zoledronic acid monohydrate from the reaction        mixture.

The present invention is illustrated by examples and not to be construedas limiting.

EXAMPLES Example 1

Preparation of Alendronic Acid Monosodium Trihydrate

A suspension of 4-aminobutyric acid (25 g, 0.242 mol) and phosphorousacid (29.8 g, 0.364 mol) in sulfolane (90 ml) was heated to 75° C. for30 min. The mixture was cooled to 35-40° C. and then graduallyintroduced phosphorous trichloride (72 ml, 0.824 mol) while maintainingthe temperature between 35-45° C. The mixture was heated to 63-67° C.for 3 hours whereby a thick white mass resulted. It was then cooled to0-5° C. and quenched by slow addition of water (250 ml) over a period of1 hr. The resulting clear solution is heated at 100° C. for 3 hrs,cooled to ambient temperature and charcoalized. To the charcoalizedsolution is added 45% w/w sodium hydroxide solution at 0-5° C. until pHis 4.3. The mixture is then stirred for 3 hrs at 0-5° C. and thecrystallized product is filtered, washed sequentially with chilled water(100 ml), rectified spirit (75 ml) and dried in air oven at 55-60° C.until water content is between. 16-18% w/w. Yield 54 g, (68.5%),appearance: white crystalline solid, purity>99.0%.

Example 2

Preparation of Pamidronic Acid

A suspension of 3-aminopropionic acid (25 g, 0.280 mol) and phosphorousacid (34.5 g, 0.421 mol) in sulfolane (90 ml) is heated to 75° C. for 30min. The mixture is cooled to 35-40° C. and then gradually introducedphosphorous trichloride (83 ml, 0.954 mol) while maintaining thetemperature at 35-45° C. The mixture is heated to 63-67° C. for 3 hrs,whereby white solid results. It is then cooled to 0-5° C. and quenchedby slow addition of water (250 ml) at 0-5° C. over a period of 1 hr. Theresulting clear solution is charcoalized and is heated at 100° C. for 3hrs, cooled to ambient temperature. Cooled the charcoalized solution andstirred for 4 hrs at 0-5° C. The crystallized product is filtered,washed sequentially with chilled water (100 ml), rectified spirit (75ml) and dried in air oven at 55-60° C. until water content is less than0.5% w/w. Yield 41.4 g, (62.7%), appearance: white crystalline solid,purity>99.0%.

Example 3

Preparation of Pamidronic Acid Disodium Pentahydrate

To a stirred suspension of pamidronic acid (25 g) in water (200 ml) isadded 20% w/w sodium hydroxide solution at 20-25° C. until pH is 8.0.The resulting mixture is stirred for 4 hours at 20-25° C. and then for 1hour at 2-5° C. The crystallized product is filtered, washed withchilled water (50 nm) and dried in air oven at 55-60° C. until watercontent is between. 23-27% w/w. Yield 30 g, (76.4%), appearance: whitecrystalline solid, purity >99.0%.

Example 4

Preparation of Risedronic Acid

A suspension of 3-pyridylacetic acid hydrochloride (50 g, 0.288 mol) andphosphorous acid (35.4 g, 0.432 mol) in sulfolane (180 ml) is heated to75° C. for 30 min. The mixture is cooled to 35-40° C. and then graduallyintroduced phosphorous trichloride (85.6 ml, 0.98 mol) while maintainingthe temperature between 35-45° C. The mixture is heated to 63-67° C. for3 hours whereby a thick white mass results. It is then cooled to 0-5° C.and quenched by slow addition of water (500 ml) at 0-5° C. over a periodof 1 hour. The resulting clear solution is charcoalized and heated at100° C. for 3 hrs, cooled to ambient temperature and then cooled 0-5° C.After stirring for 2 hrs at 0-5° C. the crystallized product isfiltered, washed sequentially with chilled water (100 ml), rectifiedspirit (75 ml) and dried in air oven at 55-60° C. until loss on dryingis less than 0.5% w/w. Yield 60.4 g, (70.47%), appearance: whitecrystalline solid, purity>99.0%.

Example 5

Preparation of Risedronic Acid Monosodium

To a stirred suspension of risedronic acid (25 g) in water (200 ml) isadded 20% w/w sodium hydroxide solution at 0-5° C. until pH is 4.3. Theresulting mixture is stirred for 2 hrs at 0-5° C. The crystallizedproduct is filtered, washed sequentially with chilled water (50 ml) andrectified spirit (50 ml), dried in air oven at 55-60° C. until loss ondrying is between. 13.5-16.5% w/w. Yield 30 g, (76.4%), appearance;white crystalline solid, purity >99.0%.

Example 6

Preparation of Zoledronic Acid Monohydrate

A suspension of 1-imidazolylacetic acid (50 g, 0.396 mol) andphosphorous acid (48.7 g, 0.594 mol) in sulfolane (180 ml) is heated to75° C. for 30 min. The mixture is cooled to 35-40° C. and then graduallyintroduced phosphorous trichloride (117 ml, 1.346 mol) while maintainingthe temperature between 35-45° C. The mixture is heated to 63-67° C. for3 hrs, whereby white solid results. It is then cooled to 0-5° C. andquenched by slow addition of water (500 ml) at 0-5° C. over a period of1 hr. The resulting clear solution is heated at 100° C. for 3 hrs,cooled to ambient temperature and charcoalized. To the charcoalizedsolution is added acetone (800 ml). The mixture is then stirred for 4hrs at 20-25° C. and the crystallized product is filtered, washedsequentially with chilled water (200 ml), acetone (100 ml) and dried inair oven at 55-60° C. until water content is between. 6.2-7.2% w/w.Yield 81.3 g, (70.7%), appearance: white crystalline solid.

Example 7

Preparation of Zoledronic Acid Monohydrate

A suspension of 1-imidazolylacetic acid (20 g, 0.159 mol) andphosphorous acid (19.6 g, 0.239 mol) in 1,2-dimethoxyethane (72 ml) isheated to 75° C. for 30 minutes. The mixture is cooled to 35-40° C. andthen gradually introduced phosphorous trichloride (48 ml, 0.543 mol)while maintaining the temperature between 35-45° C. The mixture isheated to 63-67° C. for 3 hrs, whereby white solid results. It is thencooled to 0-5° C. and quenched by slow addition of water (160 ml) at0-5° C. over a period of 1 hr. The resulting clear solution is heated at100° C. for 3 hrs, cooled to ambient temperature and charcoalized. Tothe charcoalized solution is added acetone (320 ml). The mixture is thenstirred for 4 hours at 20-25° C., the crystallized product is filtered,washed sequentially with chilled water (80 ml), acetone (80 ml) anddried in air oven at 55-60° C. until water content is between 6.2-7.2%w/w. Appearance: white crystalline solid, purity>99.5%, meetingspecification as per IHS.

1. A process for preparation of bisphosphonic acid, a compound offormula 1 or a salt thereof,

comprising reacting a carboxylic acid compound of formula 2 or a saltthereof

wherein, A is a straight chain alkyl, a branched alkyl or a cyclic alkylchain with up to 10 carbon atoms, which can optionally contain heteroatoms in between and, B is alkyl, aralkyl, aromatic or heteroaromaticgroup, which can be optionally substituted; or

wherein, R₁ and R₂ may be selected from hydrogen or straight chain,branched or cyclic lower alkyl, with phosphorous acid and a phosphorouschloride selected from PCl₃, PCl₅ and POCl₃, in sulfolane.
 2. Theprocess as claimed in claim 1, wherein the carboxylic acid is4-aminobutyric acid and the bisphosphonic acid is alendronic acid. 3.The process as claimed in claim 1, wherein the carboxylic acid is3-aminopropionic acid and the bisphosphonic acid is pamidronic acid. 4.The process as claimed in claim 1, wherein the carboxylic acid is3-pyridylacetic acid and the bisphosphonic acid is risedronic acid. 5.The process as claimed in claim 1, wherein the carboxylic acid is1-imidazolylacetic acid and the bisphosphonic acid is zoledronic acid.6. The process as claimed in claim 1, wherein the carboxylic acid isN-(n-pentyl)-N-methyl-3-aminopropionic acid and the bisphosphonic acidis ibandronic acid.
 7. The process as claimed in claim 1, wherein thecarboxylic acid is 2-(imidazo[1,2-a]pyridin-2-yl)ethanoic acid and thebisphosphonic acid is minodronic acid.
 8. The process as claimed inclaim 1, wherein the carboxylic acid is 6-aminohexanoic acid and thebisphosphonic acid is neridronic acid.
 9. The process as claimed inclaim 1, wherein the carboxylic acid is 3-(dimethylamino)propionic acidand the bisphosphonic acid is olpadronic acid.